Lysosomal storage disorders are a group of autosomal recessive diseases caused by the accumulation of cellular glycosphingolipids, glycogen, or mucopolysaccharides, due to defective hydrolytic enzymes. Examples of LSDs include but are not limited to Gaucher disease (Beutler et al., The Metabolic and Molecular Bases of Inherited Disease, 8th ed 2001 Scriver et al., ed. pp. 3635-3668, McGraw-Hill, New York), GM1-gangliosidosis (id. at pp 3775-3810), fucosidosis (The Metabolic and Molecular Bases of Inherited Disease 1995. Scriver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D., ed pp. 2529-2561, McGraw-Hill, New York), mucopolysaccharidoses (id. at pp 3421-3452), Pompe disease (id. at pp. 3389-3420), Hurler-Scheie disease (Weismann et al., Science. 1970; 169, 72-74), Niemann-Pick A and B diseases, (The Metabolic and Molecular Bases of Inherited Disease 8th ed. 2001. Scriver et al. ed., pp 3589-3610, McGraw-Hill, New York), and Fabry disease (id. at pp. 3733-3774). Others include Metachromatic Leukodystrophy, Kuf's Disease (Adult Neuronal Lipoid Lipofucsinosis) and Adrenoleukodystrophy. Each LSD is associated with a specific defective hydrolytic enzyme caused by one or more mutations which cause the enzyme to become conformationally unstable in the ER following synthesis, and thus, become targeted for degradation instead of trafficking through the Golgi to the native location in the lysosome.
Several LSDs have significant neurological involvement. For example, Gaucher disease is the most common LSD that is associated with the accumulation of glycosphingolipids (GSL) in cells, particularly monocytes and macrophages, of afflicted individuals. This aberrant build up of GSL results from a genetic deficiency (mutation) in the lysosomal enzyme acid β-glucosidase (Gba; glucocerebrosidase), the lysosomal hydrolase that breaks down the GSL glucosylceramide (GluCer). The disease has been classified into three clinical types, depending on neurological involvement and disease severity (Cox et al., Q J Med. 2001; 94: 399-402). Type 2 Gaucher disease is the rarest, most severe form, and is associated with early onset of acute neurologic disease. The characteristic feature of neuronopathic Gaucher disease is an abnormality of horizontal gaze. Afflicted patients develop progressive encephalopathy and extrapyrimidal symptoms such as rigidity and Parkinson's-like movement (parkinsonism). Most Type 2 Gaucher patients die in early childhood from apnea or aspiration due to neurological deterioration.
Type 3 Gaucher disease also has neurological involvement, although to a lesser extent than Type 2. Type 3 patients have central nervous system symptoms that include poor coordination of movements (ataxia), seizures, paralysis of the eye muscles, epilepsy, and dementia. A sub-classification of Type 3, Type 3c, is associated with hepatosplenomegaly, corneal opacities, progressive ataxia and dementia, and cardiac valve and aortic root calcification.
Other LSDs with neurological involvement include GM1 gangliosidosis, which is associated with mutant β-galactosidase and results in neuronal lipidosis; GM2 gangliosidosis (Tay-Sachs disease), which is associated with mutant hexosaminidase A and results in neuronal lipidosis; Niemann-Pick Disease, which is associated with mutant sphingomyelinase and also results in neuronal lipidosis; (Krabbe disease) galactocerebrosidase leukodystrophy; and neuronal ceroid lipofuscinoses, which is associated with mutant lysosomal proteases and results in neuronal lipidosis. Metachromatic Leukodystrophy is a deficiency of the enzyme arylsulfatase A and patients' symptoms include progressive movement disorders, seizures, cognitive disorders and also schizophrenia and psychiatric problems in addition to gastrointestinal disturbances. Kuf's Disease (Adult Neuronal Lipoid Lipofucsinosis) can manifest as psychiatric symptoms and seizures. Adrenal Leukodystrophy is a disorder which is characterized by progressive white-matter demyelination of the central nervous system and adrenocortical insufficiency.